The present invention relates to a novel inorganic salt of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanylchloride having the formula (I): ##STR3## and a process for preparing the same. The inorganic salt is extremely useful as an intermediate for preparing various amino acid derivatives such as N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine derivative having the general formula (II): ##STR4## wherein R.sup.1 is cycloalkyl, cycloalkylalkyl, indanyl or substituted indanyl group having 1 to 15 carbon atoms or alkoxy forms thereof; R.sup.2 and R.sup.3 are the same or different from each other and are hydrogen atom, a substituted or unsubstituted alkyl, aralkyl or aryl group having 1 to 7 carbon atoms; R.sup.1 and R.sup.2 may form a monocyclic, bicyclic or tricyclic heterocyclic ring having 1 to 15 carbon atoms together with the atoms to which they are linked; and an asterisk represents S-configuration with respect to an asymmetric carbon atom, which is expected to be an antihypertensive agent due to an excellent Angiotensin Converting Enzyme (ACE) inhibitory activity.
It is known that an Angiotensin Converting Enzyme inhibiting agent (hereinafter referred to as "ACEI") of the general formula (II), which is the final desired compound of the invention, has been prepared by, for instance, reductive amination reaction using ethyl .alpha.-oxo-.gamma.-phenylbutyrate (IV) and a peptide containing L-alanine having the general formula (III): ##STR5## wherein R.sup.1, R.sup.2 and R.sup.3 are as defind above.
In case of enalapril or 'N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline which is one of the typical ACEI, it is known to be prepared by reducing a Schiff's base (VI), which is prepared by condensation reaction by dehydration between L-alanyl-L-proline (V) and ethyl .alpha.-oxo-.gamma.-phenylbutyrate (IV), by hydrogen gas with a catalyst such as palladium/carbon or sodium cyanoborohydride (NaBH.sub.3 CN) [Japanese Unexamined Patent Publication No. 81845/1980 and J. Org. Chem. 49 (15), 2816 (1984)]. ##STR6##
On the other hand, as a method utilizing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, there have been known a so called active esterification method in which a base having the general formula (VII): ##STR7## wherein R.sup.1 and R.sup.2 are as defined above, is condensed with 1-hydroxybenzotriazol (HOBt)/dicyclohexylcarbodiimide (DCC) [DCC-HOBt method] or with N-hydroxysuccinimide (HOSu)/DCC [DCC-HOSu method] (Japanese Unexamined patent Publications No. 161372/1981, No. 172367/1983 and No. 65057/1984, and the like); a so called mixed acid anhydride method in which the base (VII) is reacted with diethylcyanophosphate or phosphine acid anhydride (Japanese Unexamined Patent Publications No. 231052/1984 and No. 89497/1985, and the like).
As a general method for synthesizing a peptide bond, there have been known an azide method, a NCA method, an acid cloride method and the like, in addition to the above methods, as described in "Elements and Experiments of Peptide Synthesis" by Nobuo Izumiya. However, it has not yet been reported that ACEI (II) is synthesized by the acid chloride method using N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine.
As a general method for synthesizing acid chlorides, there has been well known a reaction of carboxylic acid with an inorganic halogen compound such as phosphoryl chloride, thionyl chloride, phosphorus pentachloride or phosphorus trichloride in an inert solvent. However, a process for preparing the object compound of the present invention, N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanylchloride has not yet been reported.
ACE inhibitory activity of the various amino acid derivatives (II) is closely related to the configuration at the asymmetric carbon atom. For the desired activity, it is necessary that the derivative (II) is an optically active compound with (S)-configuration with respect to the all three asymmetric carbon atoms, i.e. (SSS) form. According to the above method for synthesizing ACEI (II) by the reductive amination reaction, however, a mixture of (SSS)-configuration and (RSS)-configuration is prepared since both (S)-configuration and (R)-configuration are produced with respect to the asymmetric carbon atom in the phenylbutyric acid part of the compound produced by the reduction of the Schiff's base having the formula (VI). Therefore, a complicated optical resolution procedure is required in order to obtain the desired compound with (SSS)-configuration, and moreover, the yield of the desired compound with (SSS)-configuration is quite low, i.e. less than 50% due to the production of a large amount of the compound with (RSS)-configuration, although each reaction proceeds in high efficiency. Therefore, starting materials which are expensive and prepared by many steps, ethyl .alpha.-oxo-.gamma.-phenylbutyrate (IV) and L-alanyl-L-proline, may be wasted by this method. Also, in the reductive amination reaction, since the Schiff's base prepared in the reaction substantially has a tendency to undergo racemization, it has been attempted to prepare the Schiff's base in situ in the reduction system in order to avoid the racemization of the Schiff's base. However, ethyl .alpha.-oxo-.gamma.-phenyl butyrate (IV), which is easily reduced by nature, is not only used for producing the Schiff's base but also reduced to form a by-product such as ethyl .alpha.-hydroxy-.gamma.-phenylbutyrate, which results in a competitive wasteful consumption of the compound (IV), and thus a 2 to 3 times molar amount of the stoichiometric amount of ethyl .alpha.-oxo-.gamma.-phenylbutyrate must be used, which leads to a disadvantage in an operation such that the complicated extraction procedure required for isolating the desired compound from the reaction mixture including a large amount of ethyl .alpha.-hydroxy-.gamma.-phenylbutyrate by-produced.
With respect to the active esterification method utilizing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, it has been known that both the DCC-HOBt method and DCC-HOSu method have defects such as difficulty in removing the by-produced dicyclohexyl urea, employment of the expensive reagents in a large amount, requirement of the complicated procedure, and a yield of from only 50 to 75%. Also, serious allergy to DDC is known and thus DCC is not an industrially preferable reagent.
In the mixed acid anhydride method, a compound which is expensive and has strong toxicity, such as diethyldiaminophosphate, diphenylphosphoryl azide or alkylphosphine acid anhydride is used in order to form the mixed acid anhydride (MA) with N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, and thus the method is not also preferable in viewpoint of economy, operability and disposal of waste fluid.
As mentioned above, the conventional method for preparing ACEI (II) is not efficient in viewpoint of economy and operability.
The present inventors previously have filed a patent application for a process for preparing economically and efficiently N-[1(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl]-L-alanine and N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, which are quite useful as the intermediate for preparing ACEI (II) (Japanese Patent Application No. 19483/1985).
The present inventors have studied in order to establish a process for preparing ACEI economically and efficiently by effectively utilizing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine with the (SS)-configuration, which is easily prepared by the above-mentioned technique and is a common constituent of ACEI (II). As a result, it has been found that an inorganic acid salt of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanylchloride, which is one of the reactive derivatives of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine, can be prepared almost quantitatively by the reaction between phosphorus pentachloride and an inorganic acid salt of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine and that the obtained compound can be quite effectively utilized in the synthesis of various ACEI having the general formula (II).